ESRRA-C11orf20 Is a Recurrent Gene Fusion in Serous Ovarian Carcinoma
Open Access
- 20 September 2011
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLoS Biology
- Vol. 9 (9), e1001156
- https://doi.org/10.1371/journal.pbio.1001156
Abstract
Every year, ovarian cancer kills approximately 14,000 women in the United States and more than 140,000 women worldwide. Most of these deaths are caused by tumors of the serous histological type, which is rarely diagnosed before it has disseminated. By deep paired-end sequencing of mRNA from serous ovarian cancers, followed by deep sequencing of the corresponding genomic region, we identified a recurrent fusion transcript. The fusion transcript joins the 5′ exons of ESRRA, encoding a ligand-independent member of the nuclear-hormone receptor superfamily, to the 3′ exons of C11orf20, a conserved but uncharacterized gene located immediately upstream of ESRRA in the reference genome. To estimate the prevalence of the fusion, we tested 67 cases of serous ovarian cancer by RT-PCR and sequencing and confirmed its presence in 10 of these. Targeted resequencing of the corresponding genomic region from two fusion-positive tumor samples identified a nearly clonal chromosomal rearrangement positioning ESRRA upstream of C11orf20 in one tumor, and evidence of local copy number variation in the ESRRA locus in the second tumor. We hypothesize that the recurrent novel fusion transcript may play a role in pathogenesis of a substantial fraction of serous ovarian cancers and could provide a molecular marker for detection of the cancer. Gene fusions involving adjacent or nearby genes can readily escape detection but may play important roles in the development and progression of cancer. Serous ovarian cancer, the most common form of ovarian cancer, is especially lethal because it is usually only detected at a late stage in its progression, after the cancer has spread to other tissues. We searched for molecular markers of this cancer that might provide a better way to detect tumors at a curable stage and that might provide targets for new treatments. Chromosomal rearrangements that fuse two genes to produce a recombinant gene that enhances growth or spread of the cancer are particularly specific biomarkers and have been found in many cancers. By “deep” sequencing of the RNA molecules that carry genetic information in serous ovarian cancers, we discovered a rearrangement that fuses the same two neighboring genes in at least 15% of these tumors. The two fused genes are ESRRA, which encodes a key regulator of gene expression, and an essentially uncharacterized gene, C11orf20, that is normally adjacent to the ESRRA gene. Chromosomal rearrangements that recombine parts of two nearby genes or even parts of a single gene may be a common, important feature of the cancer genome that eludes detection by most approaches to characterizing cancer genomes.Keywords
This publication has 41 references indexed in Scilit:
- De novo rates and selection of large copy number variationGenome Research, 2010
- Orphan nuclear receptors in breast cancer pathogenesis and therapeutic responseEndocrine-Related Cancer, 2010
- Towards a comprehensive structural variation map of an individual human genomeGenome Biology, 2010
- Hybrid selection of discrete genomic intervals on custom-designed microarrays for massively parallel sequencingNature Protocols, 2009
- Transcriptome sequencing to detect gene fusions in cancerNature, 2009
- A large genome center's improvements to the Illumina sequencing systemNature Methods, 2008
- Mapping and quantifying mammalian transcriptomes by RNA-SeqNature Methods, 2008
- Velvet: Algorithms for de novo short read assembly using de Bruijn graphsGenome Research, 2008
- Global Survey of Phosphotyrosine Signaling Identifies Oncogenic Kinases in Lung CancerCell, 2007
- Positional stability of single double-strand breaks in mammalian cellsNature, 2007